Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-validation in two independent cohorts

PLoS One. 2018 Mar 22;13(3):e0194609. doi: 10.1371/journal.pone.0194609. eCollection 2018.

Abstract

Introduction: Effective predictive biomarkers for selection of patients benefiting from adjuvant platinum-based chemotherapy in non-small cell lung cancer (NSCLC) are needed. Based on a previously validated methodology, molecular profiles of predicted sensitivity in two patient cohorts are presented.

Methods: The profiles are correlations between in vitro sensitivity to cisplatin and vinorelbine and baseline mRNA expression of the 60 cell lines in the National Cancer Institute panel. An applied clinical samples filter focused the profiles to clinically relevant genes. The profiles were tested on 1) snap-frozen tumors from 133 patients with completely resected stage 1B-2 NSCLC randomized to adjuvant cisplatin and vinorelbine (ACV, n = 71) or no adjuvant treatment (OBS, n = 62) and 2) formalin-fixed paraffin-embedded (FFPE) tumors from 95 patients with completely resected stage 1A-3B NSCLC receiving adjuvant cisplatin and vinorelbine.

Results: The combined cisplatin and vinorelbine profiles showed: 1) univariate Hazard Ratio (HR) for sensitive versus resistant of 0.265 (95% CI:0.079-0.889, p = 0.032) in the ACV cohort and a HR of 0.28 in a multivariate model (95% CI:0.08-1.04, p = 0.0573); 2) significant prediction at 3 year survival from surgery in univariate (HR = 0.138 (95% CI:0.035-0.537), p = 0.004) and multivariate analysis (HR = 0.14 (95% CI:0.030-0.6), p = 0.0081). No discrimination was found in the OBS cohort (HR = 1.328, p = 0.60). The cisplatin predictor alone had similar figures with 1) univariate HR of 0.37 (95% CI:0.12-1.15, p = 0.09) in the ACV cohort and 2) univariate HR of 0.14 (95% CI:0.03-0.59, p = 0.0076) to three years. Functional analysis on the cisplatin profile revealed a group of upregulated genes related to RNA splicing as a part of DNA damage repair and apoptosis.

Conclusions: Profiles derived from snap-frozen and FFPE NSCLC tissue were prognostic and predictive in the patients that received cisplatin and vinorelbine but not in the cohort that did not receive adjuvant treatment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung / diagnosis*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / surgery
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Cisplatin / therapeutic use*
  • Cohort Studies
  • Datasets as Topic
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / diagnosis*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / surgery
  • Male
  • Middle Aged
  • Molecular Diagnostic Techniques / methods*
  • Prognosis
  • Randomized Controlled Trials as Topic
  • Transcriptome*
  • Treatment Outcome

Substances

  • Biomarkers, Tumor
  • Cisplatin

Grants and funding

This work was supported by The Market Development Fund, Denmark, 13/03015, (https://markedsmodningsfonden.dk/in_english); Innovation Fund Denmark, grant 5139-00026B (IKB), (https://innovationsfonden.dk/); Danish Cancer Society research scholarship R84-A5565 (IKB) (https://www.cancer.dk/forskning/stoette-til-forskning/dlnu/). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Anker Hansen, Thomas Jensen, Bruce Pratt, Peter Buhl Jensen and Steen Knudsen are employed by Oncology Venture Aps. Oncology Venture Aps provided support in the form of salaries for authors AH, TJ, BP, PBJ, SK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Ida Kappel Buhl, Anker Hansen, Thomas Jensen, Jon Askaa, Peter Buhl Jensen and Steen Knudsen are employed by Medical Prognosis Institute A/S. Medical Prognosis Institute A/S provided support in the form of salaries for authors IKB, AH, TJ, JA, PBJ, SK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.